Peripheral arterial disease (PAD) is a highly prevalent, frequently morbid manifestation of systemic atherosclerosis, but relatively little attention has been paid to the epidemiology and risk factors for PAD. Endothelial dysfunction and its relationship with oxidative stress, inflammation, and renal insufficiency may be a critically important pathway in the development and prognosis of PAD. Endothelial dysfunction has been frequently observed among patients with PAD, and emerging studies suggest it may prospectively predict PAD, but large prospective studies of the roles of endothelial function, oxidative stress, inflammation, and renal function in the development of PAD are lacking. We propose a multi-faceted approach to evaluate the roles of endothelial function, oxidative stress, and their correlates in the development of PAD, using two well-defined, large, and carefully followed cohorts of U.S. men and women - the Nurses'Health Study and the Health Professionals Follow-up Study. Both studies include over 20 years of repeated dietary and lifestyle questionnaire data, blood samples collected from subsamples of 32,826 women in NHS and 18,225 men in HPFS, and prospectively reported cases of clinically important PAD. The current proposal will use these rich resources to examine several markers related to endothelial function and oxidative stress, their interrelationships with each other and other cardiovascular risk factors, and their associations with development of PAD. Endothelial dysfunction is measured by intercellular adhesion molecule-1. Markers of oxidative stress include oxidized phospholipids present on apoB particles and [unreadable]-glutamyl transferase. Serum markers related to renal dysfunction include cystatin-C and [unreadable]-2 microglobulin. Finally, we will examine how a derived dietary antioxidant score, based upon measured oxidative potential of specific foods using the ferric-reducing/antioxidant power method, is related to PAD.